While small extracellular vesicles (sEVs)-derived circular RNAs (circRNAs) have been emerged as significant players in cancer, the function and underlying mechanism of sEVs-derived circRNAs in anti-cancer immunity remain unclear.
Gastric cancer (GC)-derived circRNAs were identified using RNA-seq data from GEO datasets and quantitative reverse transcription polymerase chain reaction (qRT-PCR), RNA immunoprecipitation, dual-luciferase assay, and bioinformatics analysis were performed to investigate the regulatory axis. Transwell assay, wound healing assay, cell counting kit-8 (CCK-8) assay, and xenograft models were used to evaluate its role in GC progression in vivo and in vitro. The delivery of specific circRNAs into sEVs were verified through electron microscopy, nanoparticle tracking analysis (NTA) and fuorescence in situ hybridization (FISH). Flow cytometric analysis and immunohistochemical staining were conducted to find out how specific circRNAs mediated CD8+ T cell exhaustion and resistant to anti-programmed cell death 1 (PD-1) therapy.
We identified that circ_0001947, packaged by GC-derived sEVs, was obviously elevated in GC and was associated with poor clinical outcome. High circ0001947 level augmented the proliferation, migration, and invasion of GC cells. Mechanistically, circ0001947 sponged miR-661 and miR-671-5p to promote the expression of CD39, which further facilitated CD8+ T cell exhaustion and immune resistance. Conversely, blocking circ_0001947 attenuated CD8+ T cell exhaustion and increased the response to anti-PD-1 therapy.
Our study manifested the therapeutic potential of targeting sEVs-transmitted circ_0001947 to prohibit CD8+ T cell exhaustion and immune resistance in GC.
© 2024. The Author(s).

T cell receptor (TCR) sensitivity to peptide-major histocompatibility complex (MHC) dictates T cell fate. Canonical models of TCR sensitivity cannot be fully explained by transcriptional regulation. In this work, we identify a posttranscriptional regulatory mechanism of TCR sensitivity that guides alternative splicing of TCR signaling transcripts through an evolutionarily ultraconserved poison exon (PE) in the RNA-binding protein (RBP) TRA2β in mouse and human. TRA2β-PE splicing, seen during cancer and infection, was required for TCR-induced effector T cell expansion and function. Tra2β-PE skipping enhanced T cell response to antigen by increasing TCR sensitivity. As antigen levels decreased, Tra2β-PE reinclusion allowed T cell survival. Finally, we found that TRA2β-PE was first included in the genome of jawed vertebrates that were capable of TCR gene rearrangements. We propose that TRA2β-PE splicing acts as a gatekeeper of TCR sensitivity to shape T cell fate.

A subset of individuals exposed to Mycobacterium tuberculosis (Mtb) that we refer to as 'resisters' (RSTR) show evidence of IFN-γ- T cell responses to Mtb-specific antigens despite serially negative results on clinical testing. Here we found that Mtb-specific T cells in RSTR were clonally expanded, confirming the priming of adaptive immune responses following Mtb exposure. RSTR CD4+ T cells showed enrichment of TH17 and regulatory T cell-like functional programs compared to Mtb-specific T cells from individuals with latent Mtb infection. Using public datasets, we showed that these TH17 cell-like functional programs were associated with lack of progression to active tuberculosis among South African adolescents with latent Mtb infection and with bacterial control in nonhuman primates. Our findings suggested that RSTR may successfully control Mtb following exposure and immune priming and established a set of T cell biomarkers to facilitate further study of this clinical phenotype.
© 2024. The Author(s).

The immunoprotective components control COVID-19 disease severity, as well as long-term adaptive immunity maintenance and subsequent reinfection risk discrepancies across initial COVID-19 severity, remain unclarified. Here, we longitudinally analyzed SARS-CoV-2-specific immune effectors during the acute infection and convalescent phases of 165 patients with COVID-19 categorized by severity. We found that early and robust SARS-CoV-2-specific CD4+ and CD8+ T cell responses ameliorate disease progression and shortened hospital stay, while delayed and attenuated virus-specific CD8+ T cell responses are prominent severe COVID-19 features. Delayed antiviral antibody generation rather than titer level associates with severe outcomes. Conversely, initial COVID-19 severity imprints the long-term maintenance of SARS-CoV-2-specific adaptive immunity, demonstrating that severe convalescents exhibited more sustained virus-specific antibodies and memory T cell responses compared to mild/moderate counterparts. Moreover, initial COVID-19 severity inversely correlates with SARS-CoV-2 reinfection risk. Overall, our study unravels the complicated interaction between temporal characteristics of virus-specific T cell responses and COVID-19 severity to guide future SARS-CoV-2 wave management.
© 2024. The Author(s).

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.
© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.